Human genetic polymorphisms in metabolic activation and detoxification pathways are a major source of inter-individual variation in susceptibility to cancer. We developed genotyping assays for the "at- risk" variants of enzymes that protect against carcinogens in cigarette smoke, diet, industrial processes and environmental pollution. Following testing of over 5000 individuals for these candidate susceptibility genes, we find that the frequency of the at-risk genotypes for glutathione transferase M1 (GSTM1), theta 1 (GSTT1), and n- acetyltransferase (NAT1 and NAT2) vary significantly between Asians, Caucasian- and African-americans. This suggests that some of the ethnic differences in cancer incidence may be due to genetic metabolic differences as well as exposure differences. In ongoing studies with researchers at the NIEHS, National Cancer Institute, Columbia University, University of North Carolina and University of Keele, England we are testing the impact of these cancer susceptibility genes in case-control studies of cancer of the bladder, lung, liver, colon, stomach, prostate, breast and the myelodysplastic syndromes. We find that a new polymorphism in the NAT1 gene affects arylamine detoxification and is associated with higher levels of DNA adducts. This common NAT1 variant is a significant genetic risk factor in cancer of the bladder, colorectum, and stomach. We are also developing new methods to assess damage from carcinogens. These studies seek to integrate environmental and genetic factors in the development of human disease.